Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity.
Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity.
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DOI：
10.1038/mto.2014.10
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Cripe TP
中科院分区：
文献类型：
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作者：
Leddon JL;Chen CY;Currier MA;Wang PY;Jung FA;Denton NL;Cripe KM;Haworth KB;Arnold MA;Gross AC;Eubank TD;Goins WF;Glorioso JC;Cohen JB;Grandi P;Hildeman DA;Cripe TP
多项研究表明，除了直接溶瘤外，病毒疗法还可促进对疗效至关重要的抗肿瘤细胞毒性T细胞应答。为了进一步研究这一现象，我们测试了三种同基因小鼠肉瘤模型，这些模型在体外对溶瘤性单纯疱疹病毒复制和细胞毒性表现出不同程度的宽容性，其中最宽容的是与一些人肉瘤肿瘤细胞系相当的。体内抗肿瘤作用的范围为无反应或中度反应至完全肿瘤消退和保护肿瘤再激发。对病毒溶瘤的体外容许性不能预测体内抗肿瘤作用，因为所有三种肿瘤均显示出完整的干扰素信号传导和对体内病毒的最小容许性。肿瘤收缩是T细胞介导的，具有最大抗肿瘤活性所需的肿瘤特异性抗原应答。先天性和适应性免疫微环境的进一步分析揭示了易感性和耐药性的潜在相关性，包括有利和不利的细胞因子谱、肿瘤内髓样细胞的差异组成以及肿瘤细胞免疫原性和肿瘤浸润T细胞亚群的基线差异。很可能需要更全面地了解免疫免疫微环境和病毒感染之间的相互作用，以充分利用这种治疗平台的抗肿瘤作用。
Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform.